Investigators in the Division of Pulmonary and Critical Care Medicine at the University of California, San Francisco hereby apply to participate in a cooperative COPD Clinical Research Network, to examine existing and novel therapies and management strategies for COPD, and to rapidly disseminate the findings of this Network to the medical community. COPD is the 4th leading cause of death in the United States, and the associated financial and social burden is enormous. As new information on the pathobiology of COPD and new approaches for management appear, large, carefully conducted, collaborative multicenter studies are required to define the position of these new strategies in our therapeutic algorithm. Two specific protocols are included in this application; both test novel therapeutic approaches to important clinical problems associated with COPD. The first proposal, "The Effects of TNF-alpha Inhibition in COPD", examines the ability of a monoclonal antibody against the potent proinflammatory cytokine TNF-alpha to reduce the rate of exacerbations in patients with moderate-to-severe COPD. Exacerbations account for most of the emergency department visits, hospitalizations, and deaths associated with COPD. This proposal will examine the effect of anti-TNF-alpha therapy on exacerbations, and the relationship between exacerbations, symptoms, lung function, quality of life, markers of inflammation in airway secretions, and expression of epithelial cell genes related to mucus production. The second project, "Inhibition of Endothelin-1 in COPD-related Pulmonary Arterial Hypertension" will examine whether treatment with the Endothelin A and B receptor antagonist bosentan improves capacity in patients with pulmonary arterial hypertension, and the prognosis for these patients is poor. Evidence suggests that the pulmonary artery lesion is not due solely to hypoxemia, and that vasodilator therapy may be beneficial. This study will test an orally-administered therapy with bosentan, and clinically-important endpoints including exercise capacity, functional class, dyspnea, quality of life, and overall clinical status.